Halogenated derivatives of



Patented Dec. 3, 1940 PATENT OFFICE azzatas HALOGENATED DERIVATIVES OFAGETOPBOPANE Edwin R. Buchman, Pasadena, Calif asaignor to chCorporation, New York, N. Y a corporation of New York No Drawing.Application June 11, 1938,

Serial No. 218.189

12 Claims. (c1. zen-ass) This invention relates to the production ofhalogenated derivatives of acetopropane and has for its objects theprovision of such derivatives and 01 useful and effective methods ofproducing 5 them; Halogenatcd compounds of the type to which thisinvention relates are useful in the synthesis of. vitamin B1 which hasextremely valuable therapeutic-and nutritional properties.

This application is a continuation in part of w my copendingapplication, Serial No. 171,905,

filed October 30, 1937, which inturn is a continuation in part of myapplications, Serial No. 11,683, filed March 18, 1935, and Serial No.98,929, filed September 1, 1936. m In accordance with the invention,halogenated derivatives of acetopropane embodying the invention may beprepared by the halogenation of such compounds as 'y acetopropyl amines,'y acetopropyl halides, 'y, acetopropyl esters, and other derivatives of'y acetopropane which may be converted into 7 acetopropyl alcoholwithout causing other modifications of the compounds.

One process embodying the invention comprises the halogenatlon of estersof 7 acetopropyl gs alcohol. A typical example of this type of reactionis the halogenation of 'y acetopropyl acetate by the action of asuliuryl halide'or by treatment with a halogen.

According to one specific process of this type 14.4 grams of 'yacetopropyl acetate (prepared by the method of Lipp. Ber. 22, 1203(1898), or by the hydrolysis of acetobutyrolactone in glacial aceticacid) arechlorinated with 15.5 grams of suliuryl chloride at C. underanhydrous con- 3g ditions for one-half hour. Then two volumes of etherare added and the resulting solution is. heated on the steam bath toremove the remaining sulfur dioxide and hydrogen chloride. The

40 made alkaline with potassium carbonate and then extracted repeatedlywith ether. The ethereal solution is first dried, over sodium sulfateand then over anhydrous potassium carbonate, after which the ether isdistilled oil? in vacuo. The

5 residue is fractionally distilled in vacuo and pure '7 chlor 'yacetopropyl acetate, which has a boiling point of 72 C. at 1 mm.pressure, is obtained. By a similar reaction 7 brom 'y acetopropylacetate may be prepared by reacting upon 7 aceto- 50 propyl acetate withsulfuryl bromide. Instead of using sulfuryl halides as the halogenatingagents, the elemental halogens may be substituted with satisfactoryresults. Thus, '7 acetopropyl acetate may be reacted upon by chlorine,bromine II and iodine to introduce these halogens in the product is thenpoured into ice water, the mixture position 01 the propyl group in thiscompound.

It is also possible to produce '7 halogen derivatives of 'y acetopropylacetate by treating or halogen derivatives 01 a aceto 7 butyrolactonewith acetic acid in the presence of a strong acid such, 5 for example,as hydrochloric acid. In this reaction the lactone is hydrolized to theacetopropyl alcohol and the latter combines with the acetic acid to formthe acetate. The halogenated lactone employed may be prepared inaccordance 10 with the method outlined in Patent 2,193,858, dated March19, 1940.

If desired, the halogenated 'y acetopropyl acetate produced inaccordance with the above described processes may be converted into thecorresponding halogenated 'y acetopropyl alcohol by hydrolysis. Forexample, the halogenated acetate may be heated with a dilute solution ofhydrochloric acid to hydrolize it into the corresponding alcohol.Conversely, the halogenated acetopropyl acetate may be obtained from thealcohol, if desired, by treating the latter with acetic acid.

Instead of employing 'y acetopropyl acetate, esters of the other commoncarboxy organic acids may be substituted. For example, the 'yacetopropyl esters of formic, propionic, butyrlc and benzoic acids maybe halogenated by reacting thereon with the sulfuryl halides andhalogens mentioned hereinabove in connection with the halogenation ofacetopropyl acetate. These resulting halogenated esters may likewise behydrolized to produce the corresponding halogenated 'y acetopropylalcohol, if desired.

The halogenated acetopropyl esters obtained 85 by practising any ofthese halogenatlng operations may have either of the followingstructures:

II I 40 CHr-C-C-CHi-CHtO COR and CHa--CHX-CHa-CH: A

i L o l Ketonic form inner other, laotone or tetrehydroiurane i'ormwhere X represents a halogen. It is also possible to visualize astraight chain enolic form oi. these compounds. It is probable that thereaction mixtures resulting from these processes contain some or all ofthese forms. Since this invention pertains primarily to the productionof halogenated compounds suitable for use in the synthesis of theantineuritic vitamin or derivatives thereof and in this synthesis thecompounds react as it they possess the form represented by the first of5 CHaCOCHXCHzCHaY where X is a halogen and Y is an amino group, ahalogen or any suitable group which may be converted into or replaced bya hydroxyl group without altering the rest of the compound. If it isdesired to produce the corresponding 1 halogen derivative of 'yacetopropyl alcohol from one of these compounds, the group or elementrepresented by Y may be converted into or replaced by a hydroxyl groupby well known methods with which persons skilled in the art arethoroughly familiar. For example, an amino group may be replaced bytreatment oi! the compound with nitrous acid and a halogen may bereplaced by treatment with potassium acetate and subsequent hydrolysisof the acetate so formed. It should be noted that when the symbol Y inthe formula CHaCOCHXCHzCHzY represents a halogen, the resulting compoundis still an ester although an ester or a hydrohalic acid instead of anester oi! an organic acid such as 'y acetopropyl acetate.

The halogenated derivatives of 'y acetopropane produced in 'accordancewith the invention may be condensed with thio iormamide in accordancewith the methodoutlined in my copending application, Serial No. 11,682,filed March 18, 1935, to produce thiazole derivatives, which may in turnenter into other reactions to produce synthetic vitamin B1 and otherrelated compounds having comparable physiological and therapeuticproperties. Thus, for example, '7 brom 'y acetopropyl alcohol may becondensed with thio formamide to produce the hydrobromide of 4-methyI-S-B-hydroxy-ethyl thiazole, while 7 chlor 40 y acetopropylacetate when so treated yields the hydrochloride of4-methyl-5-,8-acetoxy-ethylthiazole.

In view of the fact that iodine reacts less efiectively than dochlorine, bromine, sulfuryl chlo- 45 ride and sulfuryl bromide in thedirect halogenation oi! the aforementioned compounds, the 'y iodocompounds may be prepared, if desired, by replacing the chlorine orbromine in one of the 'y chlor or v brom compounds with iodine. 50 Forexample, -y chlor 'y acetopropyl acetate may be converted into the 'yiodo compound by treatment with sodium iodide.

In carrying out this procedure, 44.6 grams of '7 chlor 'y acetopropylacetate dissolved in ethyl 55 alcohol are treated with 37.5 grams ofsodium iodide, the mixture shaken and allowed to stand over night. Thealcohol is then removed by distillation in vacuo, 5-6 volume of waterare added to the residue and the solution is extracted with 60 ether.The ether is then dried and distilled oil in vacuo, leaving impure 'yiodo 'y acetopropyl acetate. This compound is rather unstable and issomewhat diflicult to isolate in pure form, but the impure compoundobtained as described here- 65 inbefore may be condensed at once withthio tormamide dissolved in ethyl alcohol to form the hydro-iodide of4-methyl-5-p-acetoxy-ethyl-thiazole in the manner described withreference to the corresponding chlorine compound.

By a similar treatment 7 iodo 'y acetopropyl alcohol may be preparedfrom the corresponding chlorine and bromine compounds by treatment ofthe latter with sodium iodide, and the other chlorinated and brominatedesters described hereinbefore may be converted into the iodo compoundsin a like manner.

What is claimed is:

1. The process of preparing halogenated derivatives of acetopropane,which comprises reacting upon a 'y acetopropyl ester of a carboxylicacid with sulfuryl chloride.

2. The process of preparing halogenated derivatives of acetopropane,which comprises reacting upon a 'y acetopropyl ester of a carboxylicacid with a halogenatlng agent from the group consisting of chlorine,bromine, iodine, sulfuryl chloride and suliuryl bromide.

3. The process of preparing halogenated derivatives 0t acetopropane,which comprises reacting upon 1 acetopropyl acetate with a halogenatingagent from the group consisting of chlorine, bromine, iodine, suliurylchloride and sulfuryl bromide.

4. The process of preparing a 'y chlor derivative of acetopropane, whichcomprises reacting upon '7 acetopropyl acetate with suliuryl chloride.

5. The process of preparing halogenated derivatives of 'y acetopropylalcohol which comprises making a 'y halogen derivative of a 'yacetopropyl ester of a carboxylic acid, in which the halogen is a memberof the group chlorine, bromine and iodine, and replacing the esterportion 01' the resulting compound by the hydroxyl group.

6. The process of preparing halogen derivatives of y acetopropyl alcoholwhich comprises treating a '1 acetopropyl ester oi. a carboxylic acidwith a halogenating agent from the group consisting of chlorine.bromine, iodine, sulfuryl chloride and sulfuryl bromide, and hydrolizingthe resulting compound.

7. The process of preparing a halogenated derivative of 'y acetopropylalcohol which comprises hydrolizing a 'y halogen derivative of 'yacetopropyl acetate in which the halogen is a member of the groupchlorine, bromine and iodine.

8. A chemical compound falling within the group consisting of the '7chlor, 'y brom, and 'y iodo derivatives 01' 'y acetopropyl acetate.

9. The chemical compound 7 chlor '7 acetopropyl acetate.

10. The chemical compound 7 brom 'y aceto-,

propyl acetate.

11. The chemical compound '7 iodo 'y acetopropyl acetate.

12. A chemical compound falling within the group consisting of the 'ychlor, 7 brom, and 'y iodo derivatives of -y acetopropyl esters ofcarboxylic acids.

EDWIN R. BUCHMAN.

